E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Higher-Risk Myelodysplastic Syndromes (MDS) Chronic Myelomonocytic Leukemia (CMML) Low-Blast Acute Myelogenous Leukemia (AML) |
|
E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS) are characteristed by changes to blood composition including reductions in red and white blood cells and platelets. Leukaemia is cancer of the white blood cells |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054350 |
E.1.2 | Term | Chronic myelomonocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024348 |
E.1.2 | Term | Leukemia myelogenous |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024330 |
E.1.2 | Term | Leukemia acute |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067387 |
E.1.2 | Term | Myelodysplastic syndrome transformation |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009018 |
E.1.2 | Term | Chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared with single-agent azacitidine. (An event is defined as death or transformation to acute myeloid leukemia (AML) in patients with MDS or CMML, whichever occurs first, and is defined as death in patients with low-blast AML.)
|
|
E.2.2 | Secondary objectives of the trial |
To determine whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent azacitidine. To determine whether the combination of pevonedistat and azacitidine improves 6-month and 1-year survival rates when compared to single-agent azacitidine. To determine in patients with HR MDS,patients with HR CMML, and patients with HR MDS/CMML whether the combination of pevonedistat and azacitidine delays time to AML transformation when compared to single-agent azacitidine. (Please refer to protocol for detailed list) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female patients 18 years or older.
2.Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with WBC <13,000/µL) or low-blast AML based on 1 of the following: French-American-British (FAB) Classifications: - RAEB, defined as having 5% to 20% myeloblasts in the bone marrow. - CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. OR World Health Organization (WHO) Classifications: - Refractory anemia with excess blasts-1 (RAEB-1), defined as having 5%-9% myeloblasts in the bone marrow. - Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-19% blasts in the blood. - Chronic Myelomonocytic Leukemia-2 (CMML-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-19% blasts in the blood. - Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these patients may enroll only if bone marrow blasts ≥5%). - WHO-defined AML with 20%-30% myeloblasts in the bone marrow (defined in this protocol as low-blast AML) and ≤30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine-based therapy.
3. All patients with MDS or CMML must also have one of the following Prognostic Risk Category, based on the Revised International Prognostic Scoring System (IPSS-R): - Very high (>6 points), - High (>4.5 – 6 points), or - Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of ≥5% bone marrow myeloblasts.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
5. Patients with AML (20%-30% blasts) must have a TRM score ≥4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers Calculation of TRM score: - 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age ≥71 years). - + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1). - + 0 for (platelets <50), +1 for (platelets ≥50).
6. Female patients who: - Are postmenopausal for at least 1 year before the Screening visit, OR - Are surgically sterile, OR - If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who: - Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half-lives) after the last dose of study drug, or - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
7. Ability to undergo the study-required bone marrow sample collection procedures.
8. Suitable venous access for the study-required blood sampling (ie, including PK and pharmacodynamic sampling).
9. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug): - Albumin >2.7 g/dL. - Total bilirubin ≤ the upper limit of the normal range (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤1.5×ULN of the direct bilirubin. - ALT and AST ≤2.5×ULN. - Creatinine clearance ≥50 mL/min. - Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. |
|
E.4 | Principal exclusion criteria |
1. Previous treatment for HR MDS or CMML, or low-blast AML with chemotherapy or other antineoplastic agents including HMAs such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
3. Patients with AML with a WBC count >50,000/ μL. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
4. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors: - Age >75. - Comorbidities. - Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% blasts and TRM ≥4). - Physician decision (eg, lack of available stem cell donor). The reason a patient is not eligible should be documented in the electronic case report form (eCRF).
5. Patients with either clinical evidence of or history of central nervous system involvement by AML.
6. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures or could limit expected patient survival to less than 6 months.
7. Treatment with any investigational products or participation in any interventional studies within 14 days before the first dose of any study drug.
8. Known hypersensitivity to pevonedistat or its excipients.
9. Known hypersensitivity to azacitidine or its excipients.
10. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
11. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery.
12. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
13. Life-threatening illness unrelated to cancer.
14. Prothrombin time (PT) or aPTT >1.5×ULN or active uncontrolled coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
15. Known human immunodeficiency virus (HIV) seropositive.
16. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
17. Known hepatic cirrhosis or severe preexisting hepatic impairment.
18. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
19. Treatment with strong CYP3A inducers within 14 days before the first dose of pevonedistat.
20. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
21. Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
22. Male patients who intend to donate sperm or father a child during the course of this study or for 6 months after receiving their last dose of study drug(s). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- EFS: time from randomization to the date of an EFS event (defined as death or transformation to AML in patients with MDS or CMML, whichever occurs first, and defined as death in patients with low-blast AML). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
- EFS is defined as the time from randomization to the occurrence of an event. - ORR by cycle 6 (28 day cycles). |
|
E.5.2 | Secondary end point(s) |
- OS. - 6-month and 1-year survival rates. - Time to AML transformation in patients with HR MDS, patients with HR CMML, and patients with HR MDS/CMML. - Rate of CR (CR in patients with HR MDS or CMML, CR+CRi in patients with low-blast AML), CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in patients with HR MDS or CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow CR+PR+HI (in patients with HR MDS or CMML), overall response, and overall response 2. Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as CR+PR+HI; overall response 2 in patients with low-blast AML is defined as CR+CRi+PR. - Duration of CR (CR for HR MDS or CMML, CR+CRi for low-blast AML), overall response (CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and overall response 2 (CR+PR+HI for HR MDS or CMML, CR+CRi+PR for low-blast AML). - Rates of RBC and platelet transfusion independence. - Duration of RBC transfusion independence, platelet transfusion independence, and platelet and RBC transfusion independence. - Time to first CR or PR (for HR MDS or CMML, or low-blast AML) and to first CR or CRi (for low-blast AML) when compared with single-agent azacitidine. - Rates of HI in patients with HR MDS, patients with HR MDS/CMML, and patients with HR CMML. - Patients who have inpatient hospital admission(s) related to HR MDS, CMML (collected through transformation to AML or until initiation of subsequent therapy, whichever occurs first) or low-blast AML (collected through initiation of subsequent therapy). - Time to PD, Relapse after CR (low-blast AML), Relapse after CR or PR (HR MDS/CMML), or Death. - HRQOL assessed using the EORTC QLQ-C30. - Plasma concentration-time data for pevonedistat. - ORR, EFS and OS in patients that have TP53 mutations, 17p deletions and/or are determined to be in an adverse cytogenetic risk group in both treatment arms.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary: - ORR by Cycle 6: The number and percentage of patients who achieved an objective response (CR+PR for patients with HR MDS or CMML, CR+CRi+PR for patients with low-blast AML) by Cycle 6. Up to 6 years - EFS: The time from randomization to the occurrence of an event. For patients with HR MDS/CMML, an event is defined as death or transformation to AML; for patients with low-blast AML, an event is defined as death. Up to 6 years Secondary: - OS: The time from randomization to death from any cause. Up to 6 years (Please refer to protocol for complete list) |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Turkey |
United States |
Belgium |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
Czechia |
Greece |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study will be considered complete after the final analysis for OS has been completed or the study has been terminated by the sponsor. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |